CELL-CULTURE MODELS FOR LEAD TOXICITY IN NEURONAL AND GLIAL-CELLS

Two goals of lead (Pb) neurotoxicity research are to identify molecula r and cellular alterations that underlie behavioral deficits and to de fine mechanisms of Pb uptake and tolerance in cells that accumulate Pb . Cell and tissue cultures are practical tools with which to pursue th ese goals, offering such advantages over in vivo methods as defined ce ll types, an extracellular environment that can be precisely manipulat ed, and direct observation. On the other hand, toxicity studies with c ultured cells also present new challenges of design and interpretation . If a living vertebrate is like an orchestra playing a Beethoven symp hony, then tissue culture is like two of the violinists playing their part alone. Historically, Pb toxicity studies with cell and tissue cul ture can be divided into an exploratory phase, an expansion phase, and a newly emerging intensification phase. In the exploratory phase, gro ss cytotoxic effects from massive Pb exposure (50-500 mu M) were chara cterized. The collective data suggest differential sensitivity to Pb t oxicity among various types of cultured neural cells, ranked as follow s from most to least sensitive: myelinating cells, neurons, and astrog lia. In addition, astroglia were shown to take up and store large amou nts of Pb intracellularly, a phenomenon resembling the Pb-sequestering ability hypothesized for mature astroglia in vivo. The mechanisms of Pb entry may involve an anion exchanger, Ca2+ channels, or some other transport process. Three ingrained problems concerning the use of cell cultures began to emerge: appropriate dose regimens, biologically rel evant forms of Pb (i.e. ionized or complexed with other molecules), an d suitable measurements: of Pb effects. These problems received scruti ny in the expansion phase, during which subcellular targets of Pb-indu ced damage were examined, specifically membranes, enzymes, and Ca-medi ated cellular processes. Investigators attempted to define a biologica lly relevant dose regimen in vitro, as well as a threshold dose below which Pb had no biological effect Effects of Pb at nanomolar concentra tions in intact cells and tissue homogenates stimulated the metamorpho sis of Pb toxicity studies in cell culture into a new phase, the inten sification phase. Alterations in discrete molecular targets, particula rly those effects in the cell that may be metabolically amplified, wil l be a major focus of this phase. Critical molecular targets for Pb-in duced injury appear to be present during neuritogenesis and/or synapto genesis. With the availability of cell culture models for neurite exte nsion and synapse formation, this area may be another focus for innova tive Pb neurotoxicity research. A third focus should be the concept of Pb tolerance, particularly in astroglia, which adapt to and tolerate the presence of intracellular lead. Given the slow turnover of Pb in t he brain, mechanisms for tolerance are of considerable importance. Unt il now, little research has been carried out on long-term exposure to Pb in culture. This issue, above all, requires attention in intensific ation phase. (C) 1993 Intox Press, Inc.